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nmdar inhibition

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https://www.readbyqxmd.com/read/27874976/etidronate-rescues-cognitive-deficits-through-improving-synaptic-transmission-and-suppressing-apoptosis-in-2-vessel-occlusion-model-rats
#1
Wen Li, Huijuan Yuan, Yao Yu, Yuen-Ki Cheong, Guogang Ren, Zhuo Yang
Vascular dementia (VD) is a neurodegenerative disorder caused by the reduction of cerebral blood flow. It shows a progressive cognitive impairment. In our previous study, we found that etidronate (ET) showed neuroprotective effects against glutamate-injured PC12 cells. Thus in this study, we aimed to observe the effects of ET on learning and memory impairment and the related mechanism in 2-vessel occlusion (2VO) model rats. Rats were administered a permanent bilateral common carotid artery occlusion to induce VD model...
November 22, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27866902/the-atypical-antipsychotic-olanzapine-disturbs-depotentiation-by-modulating-machrs-and-impairs-reversal-learning
#2
Woo Seok Song, Jin Hee Cha, Sang Ho Yoon, Young Seon Cho, Kyeong-Yeol Park, Myoung-Hwan Kim
Antipsychotic medication is an essential component for treating schizophrenia, which is a serious mental disorder that affects approximately 1% of the global population. Olanzapine (Olz), one of the most frequently prescribed atypical antipsychotics, is generally considered a first-line drug for treating schizophrenia. In contrast to psychotic symptoms, the effects of Olz on cognitive symptoms of schizophrenia are still unclear. In addition, the mechanisms by which Olz affects the neural circuits associated with cognitive function are unknown...
November 17, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27865768/regulation-of-extrasynaptic-signaling-by-polysialylated-ncam-impact-for-synaptic-plasticity-and-cognitive-functions
#3
REVIEW
Hristo Varbanov, Alexander Dityatev
The activation of synaptic N-methyl-d-aspartate-receptors (NMDARs) is crucial for induction of synaptic plasticity and supports cell survival, whereas activation of extrasynaptic NMDARs inhibits long-term potentiation and triggers neurodegeneration. A soluble polysialylated form of the neural cell adhesion molecule (polySia-NCAM) suppresses signaling through peri-/extrasynaptic GluN2B-containing NMDARs. Genetic or enzymatic manipulations blocking this mechanism result in impaired synaptic plasticity and learning, which could be repaired by reintroduction of polySia, or inhibition of either GluN1/GluN2B receptors or downstream signaling through RasGRF1 and p38 MAP kinase...
November 16, 2016: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/27862359/the-conversion-of-glutamate-by-glutamine-synthase-in-neocortical-astrocytes-from-juvenile-rat-is-important-to-limit-glutamate-spillover-and-peri-extrasynaptic-activation-of-nmda-receptors
#4
Yosra Trabelsi, Mohamed Amri, Hélène Becq, Florence Molinari, Laurent Aniksztejn
Glutamate transporters (EAATs) are important to maintain spatial and temporal specificity of synaptic transmission. Their efficiency to uptake and transport glutamate into the intracellular space depends on several parameters including the intracellular concentrations of Na(+) and glutamate, the elevations of which may slow down the cycling rate of EAATs. In astrocytes, glutamate is maintained at low concentration due to the presence of specific enzymes such as glutamine synthase (GS). GS inhibition results in cytosolic accumulation of glutamate suggesting that the conversion of glutamate by GS is important for EAATs operation...
November 12, 2016: Glia
https://www.readbyqxmd.com/read/27859797/in-vitro-and-in-vivo-effects-of-a-novel-dimeric-inhibitor-of-psd-95-on-excitotoxicity-and-functional-recovery-after-experimental-traumatic-brain-injury
#5
Jens Bak Sommer, Anders Bach, Hana Malá, Kristian Strømgaard, Jesper Mogensen, Darryl Scott Pickering
PSD-95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury (TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a novel dimeric inhibitor of PSD-95, UCCB01-147, on histopathology and long-term cognitive outcome after controlled cortical impact (CCI) in rats. As excitotoxic cell death is thought to be a prominent part of the pathophysiology of TBI, we also investigated the neuroprotective effects of UCCB01-147 and related compounds on NMDA-induced cell death in cultured cortical neurons...
November 17, 2016: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27852777/amyloid-%C3%AE-peptide-nitrotyrosination-stabilizes-oligomers-and-enhances-nmdar-mediated-toxicity
#6
Biuse Guivernau, Jaume Bonet, Victòria Valls-Comamala, Mònica Bosch-Morató, Juan A Godoy, Nibaldo C Inestrosa, Alex Perálvarez-Marín, Xavier Fernández-Busquets, David Andreu, Baldomero Oliva, Francisco J Muñoz
: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-β peptide (Aβ). Monomeric soluble Aβ can switch from helicoidal to β-sheet conformation, promoting its assembly into oligomers and subsequently to amyloid fibrils. Oligomers are highly toxic to neurons and have been reported to induce synaptic transmission impairments. The progression from oligomers to fibrils forming senile plaques is currently considered a protective mechanism to avoid the presence of the highly toxic oligomers...
November 16, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27836791/pharmacological-inhibition-of-pten-attenuates-cognitive-deficits-caused-by-neonatal-repeated-exposures-to-isoflurane-via-inhibition-of-nr2b-mediated-tau-phosphorylation-in-rats
#7
Lei Tan, Xin Chen, Wei Wang, Jianfang Zhang, Shiyong Li, Yilin Zhao, Jintao Wang, Ailin Luo
Evidence has shown that children exposed to repeated anesthesia in early childhood display long-term cognitive disabilities. However, the underlying mechanisms remain largely unclear. Our previous study has indicated the involvement of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in isoflurane-induced decrease of self-renewal capacity in hippocampal neural precursor cells. Additionally, it is demonstrated by others that PTEN inhibition could protect against cognitive impairment via reduction of tau phosphorylation in the alzheimer's disease model...
November 8, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27826117/neonatal-inhibition-of-na-k-2cl-cotransporter-prevents-ketamine-induced-spatial-learning-and-memory-impairments
#8
Ryan A Stevens, Brandon D Butler, Saurabh S Kokane, Andrew W Womack, Qing Lin
Prolonged ketamine exposure in neonates at anesthetic doses is known to cause long-term impairments of learning and memory. A current theoretical mechanism explains this phenomenon as being neuro-excitotoxicity mediated by compensatory upregulation of N-methyl-d-aspartate receptors (NMDARs), which then initiates widespread neuroapoptosis. Additionally, the excitatory behavior of GABAergic synaptic transmission mediated by GABAA receptors (GABAARs), occurring during the early neuronal development period, is proposed as contributing to the susceptibility of neonatal neurons to ketamine-induced injury...
November 5, 2016: Neurotoxicology and Teratology
https://www.readbyqxmd.com/read/27815216/pharmacological-evidence-that-a-failure-to-recruit-nmda-receptors-contributes-to-impaired-fear-extinction-retention-in-adolescent-rats
#9
Kathryn D Baker, Rick Richardson
Adolescents, both humans and rodents, exhibit a marked impairment in extinction of fear relative to younger and older groups which could be caused by a failure to efficiently recruit NMDA receptors (NMDARs) in adolescence. It is well-established that systemic administration of NMDAR antagonists (e.g., MK801) before extinction training impairs the retention of extinction in adult and juvenile rodents, but it is unknown whether this is also the case for adolescents. Therefore, in the present study we investigated the effect of pharmacologically manipulating the NMDAR on extinction retention in adolescent rats...
November 1, 2016: Neurobiology of Learning and Memory
https://www.readbyqxmd.com/read/27814790/differential-effects-of-tm4-tryptophan-mutations-on-inhibition-of-n-methyl-d-aspartate-receptors-by-ethanol-and-toluene
#10
C Thetford Smothers, John J Woodward
The voluntary use and abuse of alcohol and inhalants is a recognized health problem throughout the world. Previous studies have shown that these agents affect brain function in a variety of ways including direct inhibition of key ion channels that regulate neuronal excitability. Among these, the N-methyl-d-aspartate (NMDA) receptor is particularly important given its key role in glutamatergic synaptic transmission, neuronal plasticity and learning and memory. Previous studies from this laboratory and others have identified key residues within transmembrane (TM) domains of the NMDA receptor that appear to regulate its sensitivity to alcohol and anesthetics...
November 2016: Alcohol
https://www.readbyqxmd.com/read/27810933/nmdars-adapt-to-neurotoxic-hiv-protein-tat-downstream-of-a-glun2a-ubiquitin-ligase-signaling-pathway
#11
Matthew V Green, Stanley A Thayer
: HIV-associated neurocognitive disorder (HAND) affects about half of HIV-infected patients. Infected non-neuronal cells release neurotoxic factors such as the viral protein, transactivator of transcription (Tat), that potentiate NMDAR function. NMDARs regulate synaptic changes observed following exposure to HIV proteins, which may underlie cognitive impairment in HAND patients. Here we used patch-clamp recording to measure NMDAR-mediated currents in rat hippocampal cultures following exposure to Tat...
November 3, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27809304/extrasynaptic-nmda-receptor-induced-tau-overexpression-mediates-neuronal-death-through-suppressing-survival-signaling-erk-phosphorylation
#12
Xu-Ying Sun, Qing-Zhang Tuo, Zhen-Yu Liuyang, Ao-Ji Xie, Xiao-Long Feng, Xiong Yan, Mei Qiu, Shen Li, Xiu-Lian Wang, Fu-Yuan Cao, Xiao-Chuan Wang, Jian-Zhi Wang, Rong Liu
Intracellular accumulation of the hyperphosphorylated tau is a pathological hallmark in the brain of Alzheimer disease. Activation of extrasynaptic NMDA receptors (E-NMDARs) induces excitatory toxicity that is involved in Alzheimer's neurodegeneration. However, the intrinsic link between E-NMDARs and the tau-induced neuronal damage remains elusive. In the present study, we showed in cultured primary cortical neurons that activation of E-NMDA receptors but not synaptic NMDA receptors dramatically increased tau mRNA and protein levels, with a simultaneous neuronal degeneration and decreased neuronal survival...
November 3, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27802416/src-kinases-regulate-glutamatergic-input-to-hypothalamic-presympathetic-neurons-and-sympathetic-outflow-in-hypertension
#13
Xin Qiao, Jing-Jing Zhou, De-Pei Li, Hui-Lin Pan
The elevated sympathetic outflow associated with hypertension is maintained by increased N-methyl-d-aspartate receptor (NMDAR) activity in the paraventricular nucleus (PVN) of the hypothalamus. Synaptic NMDAR activity is tightly regulated by protein kinases, including the Src family of tyrosine kinases. We determined whether Src kinases play a role in increased NMDAR activity of PVN neurons projecting to the rostral ventrolateral medulla and in elevated sympathetic vasomotor tone in spontaneously hypertensive rats (SHRs)...
October 31, 2016: Hypertension
https://www.readbyqxmd.com/read/27801527/hif-1%C3%AE-triggers-long-lasting-glutamate-excitotoxicity-via-system-xc-in-cerebral-ischaemia-reperfusion
#14
Chia-Hung Hsieh, Yu-Jung Lin, Wei-Ling Chen, Yen-Chih Huang, Chi-Wei Chang, Fu-Chou Cheng, Ren-Shyan Liu, Woei-Cherng Shyu
Hypoxia-inducible factor 1α (HIF-1α) controls many genes involved in physiological and pathological processes. However, its roles in glutamatergic transmission and excitotoxicity are unclear. Here, we proposed that HIF-1α might contribute to glutamate-mediated excitotoxicity during cerebral ischaemia-reperfusion (CIR) and investigated its molecular mechanism. We showed that an HIF-1α conditional knockout mouse displayed an inhibition in CIR-induced elevation of extracellular glutamate and N-methyl-D-aspartate receptor (NMDAR) activation...
November 1, 2016: Journal of Pathology
https://www.readbyqxmd.com/read/27790093/synaptic-conductances-during-interictal-discharges-in-pyramidal-neurons-of-rat-entorhinal-cortex
#15
Dmitry V Amakhin, Julia L Ergina, Anton V Chizhov, Aleksey V Zaitsev
In epilepsy, the balance of excitation and inhibition underlying the basis of neural network activity shifts, resulting in neuronal network hyperexcitability and recurrent seizure-associated discharges. Mechanisms involved in ictal and interictal events are not fully understood, in particular, because of controversial data regarding the dynamics of excitatory and inhibitory synaptic conductances. In the present study, we estimated AMPAR-, NMDAR-, and GABAA R-mediated conductances during two distinct types of interictal discharge (IID) in pyramidal neurons of rat entorhinal cortex in cortico-hippocampal slices...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27775174/clinically-relevant-concentrations-of-ketamine-inhibit-osteoclast-formation-in-vitro-in-mouse-bone-marrow-cultures
#16
Erxia Du, Patrick McAllister, Venugopal Reddy Venna, Liping Xiao
Ketamine has been used safely in clinics for decades for analgesia and anesthesia. It is increasingly popular in clinical practice due to its new uses and importance for emergency procedures. It is known that ketamine is sequestered in the bone marrow and the major receptors for ketamine, noncompetitive N-methyl-d-aspartate receptors (NMDARs), are expressed in osteoclasts (OCs) and osteoblasts. However, the impact of ketamine on OCs or osteoblasts is unknown. In this study, we investigated the effects of ketamine on osteoclastogenesis and regulation of NMDARs expression in vitro...
October 24, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27769245/n-methyl-d-aspartate-receptor-activation-mediates-lung-fibroblast-proliferation-and-differentiation-in-hyperoxia-induced-chronic-lung-disease-in-newborn-rats
#17
YanRui Wang, ShaoJie Yue, ZiQiang Luo, ChuanDing Cao, XiaoHe Yu, ZhengChang Liao, MingJie Wang
BACKGROUND: Previous studies have suggested that endogenous glutamate and its N-methyl-D-aspartate receptors (NMDARs) play important roles in hyperoxia-induced acute lung injury in newborn rats. We hypothesized that NMDAR activation also participates in the development of chronic lung injury after withdrawal of hyperoxic conditions. METHODS: In order to rule out the anti-inflammatory effects of NMDAR inhibitor on acute lung injury, the efficacy of MK-801 was evaluated in vivo using newborn Sprague-Dawley rats treated starting 4 days after cessation of hyperoxia exposure (on postnatal day 8)...
October 21, 2016: Respiratory Research
https://www.readbyqxmd.com/read/27752082/inhibition-of-step61-ameliorates-deficits-in-mouse-and-hipsc-based-schizophrenia-models
#18
J Xu, B J Hartley, P Kurup, A Phillips, A Topol, M Xu, C Ononenyi, E Foscue, S-M Ho, T D Baguley, N Carty, C S Barros, U Müller, S Gupta, P Gochman, J Rapoport, J A Ellman, C Pittenger, B Aronow, A C Nairn, M W Nestor, P J Lombroso, K J Brennand
The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein tyrosine Phosphatase) is an important regulator of synaptic function. STEP normally opposes synaptic strengthening by increasing N-methyl D-aspartate glutamate receptor (NMDAR) internalization through dephosphorylation of GluN2B and inactivation of the kinases extracellular signal-regulated kinase 1/2 and Fyn. Here we show that STEP61 is elevated in the cortex in the Nrg1(+/-) knockout mouse model of schizophrenia (SZ). Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDARs from synaptic membranes and reverses behavioral deficits in Nrg1(+/-) mice...
October 18, 2016: Molecular Psychiatry
https://www.readbyqxmd.com/read/27713495/allosteric-regulation-in-nmda-receptors-revealed-by-the-genetically-encoded-photo-cross-linkers
#19
Meilin Tian, Shixin Ye
Allostery is essential to neuronal receptor function, but its transient nature poses a challenge for characterization. The N-terminal domains (NTDs) distinct from ligand binding domains are a major locus for allosteric regulation of NMDA receptors (NMDARs), where different modulatory binding sites have been observed. The inhibitor ifenprodil, and related phenylethanoamine compounds specifically targeting GluN1/GluN2B NMDARs have neuroprotective activity. However, whether they use differential structural pathways than the endogenous inhibitor Zn(2+) for regulation is unknown...
October 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27694970/glycine-triggers-a-non-ionotropic-activity-of-glun2a-containing-nmda-receptors-to-confer-neuroprotection
#20
Rong Hu, Juan Chen, Brendan Lujan, Ruixue Lei, Mi Zhang, Zefen Wang, Mingxia Liao, Zhiqiang Li, Yu Wan, Fang Liu, Hua Feng, Qi Wan
Ionotropic activation of NMDA receptors (NMDARs) requires agonist glutamate and co-agonist glycine. Here we show that glycine enhances the activation of cell survival-promoting kinase Akt in cultured cortical neurons in which both the channel activity of NMDARs and the glycine receptors are pre-inhibited. The effect of glycine is reduced by shRNA-mediated knockdown of GluN2A subunit-containing NMDARs (GluN2ARs), suggesting that a non-ionotropic activity of GluN2ARs mediates glycine-induced Akt activation. In support of this finding, glycine enhances Akt activation in HEK293 cells over-expressing GluN2ARs...
October 3, 2016: Scientific Reports
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